Sleep in the elderly is generally recognized as being of poorer quality than in younger adults. Nocturnal sleep in seniors is characterized by frequent awakenings, decreases in the quantity of deep slow wave sleep (Stages 3 and 4), and a concomitant decrease in delta frequencies in the EEG. Daytime alertness is reduced and naps are common, indicating diminution of the diurnal rhythms of sleep and wakefulness. Many of these changes in sleep architecture also occur in aged laboratory rodents. Our long-term objective is to understand the neural basis of age-related sleep dysfunction. The hypocretin/orexin (H/O) neurotransmitter system has recently been identified as being important in arousal state regulation, and degeneration of the H/O neurons has been found in human narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. Therefore, this system is an attractive target to study with respect to sleep and aging. The overall hypotheses of this proposal are that (1) the H/0 system is important in the maintenance of wakefulness; (2) a dysfunction of the H/O system occurs in the aged; and (3) this dysfunction is related to the sleep/wake disturbances characteristic of the elderly. Based on the literature, we conclude that aged rodents, like elderly humans, are a heterogenous population and differ with respect to their rate of physiological aging. Therefore, we will identify a subpopulation of aged rats having disrupted body temperature rhythms and sleep architecture and use these animals to test the following specific hypotheses: (1) an age-related decline occurs in the number of H/O cells in aged F344 rats that is correlated with disrupted sleep architecture; (2) an age-related decline occurs in the levels of H/O mRNA and/or peptides; (3) waking-related activation of H/O cells declines with age; (4) the release of H/O peptides decreases with age; (5) an age-related decline in the mRNA for the H/O receptor 1 and receptor 2 occurs in brain regions associated with wakefulness; and (6) an age-related decrease in binding to H/O receptor 1 and receptor 2 and/or G protein activation occurs in arousal-related brain regions. To address these questions, we will use a combination of in vivo physiological, neuroanatomical, molecular, and receptor pharmacological methods.